HRP940753A2 - Condensed diazepinones, process for their preparation and compositions containing them for the treatment of the central nervous system and to enhance cerebral perfusion - Google Patents

Description

The invention relates to new condensed diazepinones, to processes for their preparation and to agents containing these compounds for the treatment of diseases of the central nervous system and for promoting cerebral blood flow.

From EP-A-0 039 519 and 0 057 428 as also from USA-A3,660,380; 3,691,159; 4,213,984; 4,213,985; 4,210,648; 4,410,527; 4,424,225; 4,424,222 and 4,424,226 are already known condensed diazepinones with the properties of suppressing ulcers and suppressing the secretion of gastric juice.

In EP-A-0 156 191 (US-PS 4,550:107) and EP-A-0 312 895 it is disclosed that, compared to the compounds from the above-mentioned publications, condensed diazepinones by introducing alkylaminoacyl or dialkylaminoacyl residues can "induce completely different pharmacological properties , namely beneficial effects on heart rate. This also applies to the compounds of EP-AO 213 293, EP-A-0 254 955, EP-A-0 273 239, .EP-A-0 306 698, DE-A- 38 00 986, DE-A-38 02 334, DE-A-3 819 444, DE-A-38 20 346 and DE-A-38 20 345. Compounds from these publications based on their beneficial effects on heart rate and with regard to in that they affect gastric acid secretion suppression, salivation suppression and mydriatic effects, they are suitable as vagus stimulators for the treatment of bradycardia and bradyarrhythmias in human and veterinary medicine. Condensed diazepinones are described in EP-A-0 402 734 as agents for the treatment of central nervous system disorders. of the nervous system and for promoting cerebral blood flow. These agents are suitable for u need in geriatrics and migraine. A number of compounds described there show good transitivity of the central nervous system and can therefore be used for the treatment of diseases of the central nervous system, especially Alzheimer's disease.

According to structure-activity relationships derived so far, the presence of a terminal basic N-atom in the side chain is considered essential for muscarinic antagonists with high M2-selectivity (compare also US-PS 4,550,107, EP-A-20,402,734 and Engel et al . in J. Med. Chem. 32, 1718 (1989)).

We have now surprisingly established that by acylation of the terminal basic nitrogen atom of the side chain, bound to the amino nitrogen of the diazepine ring, high affinity M2-selective muscarinic antagonists are obtained.

In addition, compared to the previously described M2 selective antagonists, the "carboxamides" according to the invention show an improved M2/M1 ratio, i.e. the new compounds have a generally better binding affinity ratio for M2-receptors compared to M1-receptors.

Based on their M2-selectivity, the compounds according to the invention can be used for the treatment of bradycardia and bradyarrhythmias in human and veterinary medicine. Considering the beneficial effects on cerebral blood flow, the compounds are particularly suitable for use in geriatrics and migraine. As it was shown in experiments on animals (rats), they increase the learning ability of old animals.

The new condensed diazepinones according to the invention are partly highly lipophilic and thus fulfill an essential assumption for good transitivity in the brain. At the same time, this high lipophilicity leads to a rapid drop in the blood level, so that there is no effect on the heart rate. M2-selective antagonists, which show good penetration of the central nervous system and simultaneous M2/M1-selectivity, are particularly suitable for the therapy of diseases of the central nervous system, especially Alzheimer's disease.

The condensed diazepinones according to the invention have the general formula I

[image]

where

B represents one of the divalent residues

[image]

and X, l, m, n and R1 to R7 have the following meanings:

X is the group =CH, or if B represents a divalent residue (S), also a nitrogen atom;

1 is an integer of 1, 2 or 3;

m is an integer of 1 or 2;

n is an integer from 1 to 4;

R1 is a hydrogen atom or a straight group with 1 to 6 carbon atoms, or a branched alkyl group with 1 to 6 carbon atoms,

R2 is a hydrogen atom, a straight or branched alkyl group with 1 to 8 carbon atoms, a straight or branched alkenyl group with 4 to 6 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms optionally substituted with an alkyl group having 1 to 3 carbon atoms of atoms, an adamantyl group, a phenyl group, optionally substituted with one or two methyl or methoxy groups or a halogen atom, or a phenylalkyl group with 1 to 3 carbon atoms in the alkyl part, optionally substituted on the aromatic with a methyl or methoxy group or atom halogen:

R3 and R4, which may be the same or mutually different, are hydrogen atoms or halogens or methyl, ethyl, methoxy or ethoxy groups;

R5 is a hydrogen or chlorine atom or a methyl group,

R 6 and R 7 , which may be the same or mutually different, represent a hydrogen atom or an alkyl group with 1 to 3 carbon atoms, and R 7 may also be a halogen atom.

Preferred compounds of the above general formula are those in which

X is a nitrogen atom,

B is a divalent residue (S),

1 is number 2,

m is the number 1,

n represents the numbers 3 and 4,

R 1 is a straight alkyl group having 1 to 4 carbon atoms;

R2 is a branched alkyl group with 4 to 6 carbon atoms, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclopentyl, methylcyclohexyl, methylcycloheptyl or adamantium group,

R3 and R4 represent hydrogen atoms or one of these residues is a methyl group or a halogen atom, and the substituent - (CH2)n-NR1-CO-R2 is connected to position 4 of the piperidinyl ring.

Compounds in which R1 represents an ethyl group are particularly preferred.

Examples of branched alkyl or alkenyl groups include 1-methyl-ethyl, 1,1-dimethyl-ethyl, 1,1-dimethyl-propyl, 1,1-dimethyl-butyl, 1,1',3-trimethyl- butyl, 1-ethyl-1-methyl-ethyl, 1-ethyl-1-methyl-propyl, letyl-1-methyl-butyl, 1-ethyl-1,3-dimethyl-butyl, 1-propyl-1-methyl-ethyl, 1-propyl-1-methyl-propyl, 1-propyl-1-methyl-butyl, 1-ethyl-ethyl, 1,1-diethyl-ethyl, 1,1-diethyl-propyl, 1,1-dimethyl-butyl or 1, 1-dimethyl-but-3-enyl group.

The subject of the invention are also acid addition salts with inorganic or organic acids, for example with hydrochloric acid; hydrobromic acid, sulfuric acid, fumaric acid, maleic acid, malic acid, citric acid, tartaric acid.

According to the invention, new acylated diazepinones of general formula I are obtained by the following procedures:

a) By chemical conversion of basic substituted condensed diazepinones of general formula II

[image]

wherein X, B, l, m, n and R1 are defined as in the introduction, with a carboxylic acid of the general formula III

[image]

wherein R 2 is defined as mentioned above, or with reactive derivatives thereof.

Examples of carboxylic acid derivatives of general formula III capable of reactions are its esters, such as methyl, ethyl or benzyl ester, its thioesters, such as methyl or ethyl thioester, its halides, such as acid chloride, its anhydrides or imidazolides.

The chemical conversion is meaningfully carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, in a given case in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence of chloroformic acid ethyl ester , thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide; N,N'-carbonyldiimidazole or N,N'-thionylimidazole or triphenylphosphine/carbon tetrachloride, and in the given case in the presence of an inorganic base, such as sodium carbonate or a tertiary organic base, such as triethylamine or pyridine, which can simultaneously serve, as solvents, at temperatures between -25°C and 150°C preferably at temperatures between -10°C and the boiling point of the solvent used. Chemical conversion is also carried out without solvents, furthermore, the water produced during chemical conversion can be separated by azeotropic distillation, for example by heating with toluene on a water separator or by adding a drying agent, such as magnesium sulfate or molecular sieve.

Chemical transformations are carried out, for example, with acid halides in inert solvents, such as ether, toluene, methylene chloride, at temperatures between -50°C and the boiling point of the reaction mixture, preferably between 0°C and 50°C, and preferably in the presence of an agent which binds hydrogen halide, eg tertiary amine, sodium carbonate or calcium carbonate. Here, not only free amines of the general formula II can be used, but also their salts, from which the amines are liberated in situ by means of added auxiliary bases.

For example the chemical conversion can be carried out in the presence of imidazolide or carbodiimide, in a high-boiling solvent, such as xylene, at reflux temperature.

b) By acylating diazepines of general formula IV

[image]

where X and B have the above meanings, with carboxylic acid derivatives of the general formula V

[image]

in which l, m, n, R1 and R2 are defined as above, and Nu represents a nucleophilic group or a leaving group.

The chemical conversion of compounds of the general formula IV with acid derivatives of the general formula V takes place in a known manner. The leaving group Nu is a group that, together with the carbonyl group to which it is attached, forms a reactive carboxylic acid derivative. As reactive carboxylic acid derivatives, for example, acid halides, esters, anhydrides or mixed anhydrides, which are formed from salts of the corresponding acids (Nu = OH) and acid chlorides, such as phosphorus oxychloride, diphosphoric acid tetrachloride or chloroformic acid ester, or N- alkyl-2-acyloxypyridinium salts resulting from the chemical conversion of compounds of the general formula V (Nu = OH) with N-alkyl-2-halopyridinium salts.

The reaction is primarily carried out with mixed anhydrides of strong mineral acids, especially dichlorophosphoric acid. In this case, the reaction is carried out in the presence of an acid binding agent (proton acceptor). Suitable proton acceptors include, for example, alkali carbonates or hydrogen carbonates, such as sodium carbonate or potassium hydrogen carbonate; tertiary organic amines such as pyridine, triethylamine, ethyldiisopropylamine, 4-(dimethylamino)pyridine or sodium hydride. The reaction is carried out at temperatures between -25°C and 130°C in an inert solvent. Examples of suitable inert solvents include chlorinated aliphatic hydrocarbons, such as methylene chloride, 1,2-dichloroethane; open chain ethers or cyclic ethers such as diethylether, tetrahydrofuran or 1,4-dioxane; aromatic hydrocarbons, such as benzene, toluene, xylene, o-dichlorobenzene; polar aprotic solvents, such as acetonitrile, dimethylformamide or hexamethylphosphoric acid triamide: or mixtures thereof. Reaction times, depending on the amount and type of acylating agent of general formula V used, are between 15 minutes and 80 hours. It is not necessary to prepare the compounds of the general formula V in their pure forms, but it is better to produce them in the continuation of the reaction in a known manner in situ.

The thus obtained bases of the general formula I can then be converted into their acid addition salts or the obtained acid addition salts are converted into free bases or into other pharmacologically acceptable acid addition salts.

New condensed diazepinones of general formula I according to the invention contain up to 2 independent chiral carbon atoms. As a further chiral element, the acylated tricycle itself, which can be in two, is considered. mirror shape. It depends on the nature of the tricycle whether the energy barrier for inversion at that center is so high that the individual isomers are stable at room temperature so that they can be isolated. In the case of compounds of the general formula I, in which X is a nitrogen atom, and the positions adjacent to the diazepinone ring are not substituted, it was shown that the required activation energy is reduced to the extent that stereoisomers are no longer possible at room temperature. to prove, but only to isolate preparatively.

The new condensed diazepinones of the general formula I according to the invention therefore contain up to 3 chiral elements, one of which does not have a stable configuration at room temperature in the given case. Such compounds can appear in several diastereomeric forms and/or each time as enantiomeric (+)- and (-)-forms. The invention includes individual isomers and also their mixtures. Separation of individual diastereomers on the basis of different physico-chemical properties, eg by fractional recrystallization, succeeds from suitable solvents, with high-pressure liquid chromatography, column chromatography or gas chromatography.

The separation of possible racemic compounds of the general formula I can be carried out by known methods, for example using an optically active acid, such as (+)- or (-)-tartaric acid, or its derivative, such as (+)- or (-)-diacetyltartaric acid, (+)- or (-)-monomethyltartrate or (+)-camphorsulfonic acid.

According to the usual procedure for separating isomers, a racemic compound of the general formula I is chemically converted with one of the above-mentioned optically active acids in an equimolar amount in a solvent and the obtained crystalline diastereomeric salts are separated using their different solubilities. This chemical conversion can be carried out in any type of solvent, if these solvents show a sufficient difference in the solubility of the salt. Preferably, methanol, ethanol or their mixtures are used, for example in a volume ratio of 50:50. Each of the diastereomeric salts is then dissolved in water, neutralized with a base such as sodium carbonate or potassium carbonate, and thus the corresponding free compound is obtained in (+)- or (-)-form.

Only one enantiomer, i.e. a mixture of two optically active diastereomeric compounds, which fall under the general formula I, is also obtained by carrying out the syntheses described above with the corresponding enantiomers.

The starting compound of the general formula II can be prepared, for example, as follows:

(Aminoalkyl)pyridine of general formula VI

[image]

in which n and R1 are defined as above (compounds of this type are known from the literature and can partially be found on the market), are tert.butoxy-carbonylated in a known manner, resulting in compounds of the general formula VII:

[image]

By catalytic hydrogenation of these compounds according to known procedures, e.g. in an ethanol-hydrochloric acid solution and with the use of platinum(IV)-oxide as a catalyst (cf. F.F. Blicke et al., J. Org. Chemistry 26, 3258 (1961) or in glacial acetic acid in the presence of platinum(IV)-oxide (compare W.F. Minor et al., J. Med. Pharm. Chem. 5, 96, 195 ff (1962) and A. H. Sommers et al., J. Amer. Chem. Soc., 75, 57, 58 ff (1953)) compounds of the general formula VIII are obtained:

[image]

Such a compound is then chemically converted with a halogenacyl compound of the general formula IX

[image]

wherein X, B and m are as defined above and Hal represents a chlorine, bromine or iodine atom.

This amination takes place in an inert solvent at a temperature between -10°C and the boiling point of the solvent, preferably with at least 2 moles of a secondary amine of the general formula VIII or with 1 to 2 moles of a secondary amine of the general formula VIII and with an auxiliary base. Suitable solvents include, for example, chlorinated hydrocarbons such as methylene chloride, chloroform or dichloroethane; open chain ethers or cyclic ethers such as diethylether, tetrahydrofuran or dioxane; aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene or pyridine; alcohols such as ethanol or isopropanol; ketones, such as acetone; acetonitrile, dimethylformamide or 1,3-dimethyl-2-imidazolidinone. Auxiliary bases may include, for example, tertiary organic bases such as triethylamine, N-methylpiperidine, diethylaniline, pyridine and 4-(dimethylamino)pyridine, or inorganic bases such as alkaline or alkaline earth carbonates or hydrogencarbonates, hydroxides or oxides. In this case, the reaction can be accelerated by the addition of alkali iodides.

This gives a compound of the general formula X

[image]

in which the residues B, X, R1, and m and n are deined as above, and the tert.butoxylated residue is cleaved from it in a known manner using, for example, hydrobromic acid in glacial acetic acid, resulting in the compound of general formula II.

Activated carboxylic acids of the general formula are meaningfully obtained in the reaction mixture by methods known from the literature.

Diazepinones of the general formula IV are known from the literature (cf. EP-A-0.039519; EP-A-0.057.428; DE-C-1.179.943 and 1-204.680; F. Hunzicker et al., Arzneim.-Forsch. 13, 324 (1963) .

Carboxylic acid derivatives of the general formula V, in which Nu represents an alkoxy group, are obtained by chemical conversion of substituted piperidines of the general formula VIII with corresponding halogealkanoic acid esters, in a given case with the use of additional auxiliary bases, e.g. triethylamine, or catalysts, e.g. Triton B. By saponification of the obtained esters, for example with barium alkali, carboxylic acids are obtained which fall under the general formula V and in which Nu represents a hydroxyl group. The carboxylic acids obtained in this way then serve as starting materials for the preparation of derivatives with other nucleophilic groups, for example acid halides of formula V.

A further subject of the invention are drugs containing one or more condensed diazepinones of the general formula I, or their physiologically tolerable salts.

The compounds of the general formula I can be processed in a known manner into conventional pharmaceutical preparations, for example solutions, suspensions, tablets, dragees, capsules or tea preparations. The daily dose is generally between 0.02 and 5 mg/kg, preferably between 0.02 and 2.5 mg/kg, especially between 0.05 and 1.0 mg/kg of body weight, and to achieve the desired results the dose is gives as needed in the form of more, preferably 1 to 3 individual benefits.

As already mentioned in the introduction, basic substituted condensed diazepinones of the general formula I and their acid addition salts have valuable properties; they also show useful selectivity for cardiac M2-receptors and can therefore be used as vagus stimulators for the treatment of bradycardia and bradyarrhythmias in human and veterinary medicine.

From research by Charldorp and van Zwieten (see K.J. van Charldorp, dissertation "Characterisation of Muscarinic Receptors in the Vascular System", Amsterdam 1988: K.J. van Charldorp, D. Davidesko and P.S. van Zwieten, Eur. J. Pharmacol. 150, 197-199 : K. J. van Charldorp and P. A. van Zwieten, Naunyn S'chmiedeberg s Arch. Pharmacol. 339, 403408 (1989) it is known that muscarinic receptors in the basilar arteries are responsible for the contraction of M2-type vessels. Therefore, M2 antagonists can be expected to lower the tone of cerebral blood vessels and thereby increase blood flow.

Inhibition of demonstrable muscarinic receptors in cerebral vessels leads to the avoidance of contraction and the improvement or normalization of cerebral blood flow disorders caused by arteriosclerosis. The new compounds according to the invention are especially very suitable for improving or normalizing disorders of cerebral blood flow caused by arteriosclerosis.

A series of compounds of the general formula I, due to their high lipophilicity, show good transitivity of the central nervous system and are therefore additionally suitable for the therapy of diseases of the central nervous system, especially Alzheimer's disease: In senile dementia of the Alzheimer type, the degeneration of cholinergic neurons, especially in hippocampal and cortical projections, leads to a decrease in release neurotransmitter acetylcholine. Blockade of presynaptic autoreceptors interrupts the now negative feedback mechanism exerted by the neurotransmitter on intact neurons, and therefore causes increased release of acetylcholine and - associated - stimulation of postsynaptic receptors (D.C. Mash, D.Z. Flynn and Z.T. Potter, Science 228, 115-117 (1985) ); E.K. Perry et al., Can. J. Neurol. Sci. 13, 521-537 (1986); M. Sarter et al., TINS 11, 13-17 (1988)). The compounds are therefore suitable in geriatrics and significantly improve the ability to learn and remember.

To prove the beneficial effects on cerebral blood flow, we performed the following experiments.

A) Study of muscarinic receptor binding

Single Wistar rats (Chbb: strain THOM, body weight 180-220 g) were killed by a blow to the back of the head. The cerebral cortex, heart and salivary glands are removed, washed and homogenized in a twenty-fold volume of HEPES buffer (20 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, 100 mM sodium chloride, 10 mM magnesium chloride, pH 7.5) using of the Ultra-Turrax apparatus at the highest rotation of 60 g. The homogenates are diluted to 1:500 in relation to the original amount of tissue. For the binding experiment, 1 nM [3H]pirenzepine (3.22 TBq/mmole), which binds to M1-receptors of the cortex, and 0.3 nM [3H]NMS (3H-N-Me-thylscopolamine) are incubated (2, 64 TBq/mmol) for binding to heart and sputum at room temperature, for [3H]piperazine 90 minutes, for [3H]NMS 40 minutes each time with 0.35, 0.30 and 0.20 mg of protein per sample (0 .5 ml) for the heart, salivary gland and cortex. The protein concentration is determined according to the method of Lowry et al. (J. Hyol. Chem. 93, 265). Incubation is completed by rapid filtration through a mesh of glass fibers and using a Skatron Cell cell harvester. After washing twice (rinsing for 10 seconds with approx. 3 ml of liquid), the filters are air-dried, placed in mini-vials, shaken overnight with 4 ml of scintillation liquid and counted with an efficiency of 45-50% using a Packard 460C apparatus. All experiments are performed three times. Nonspecific binding was defined as radioactivity in the presence of 1 µM (-)-3-quinuclidinyl-benzylate. Binding data are analyzed by computer using the non-linear "last-square curve fitting" method (Heinzel, G., 1982, v: Pharmacokinetics during Drug Development: Data Analysis and Evaluation Techniques, eds. G. Bozler and J.M. van Rossum (Gustav-Springer-Verlag ), p. 207). Dissociation constants Ki are calculated from IC 50 values according to Cheny and Prusoff (Biochem. Pharmacol. 22, 3099 (1973)). The results are summarized in table l.

B) Central effect research

Principle:

Arecolin has both centrally and peripherally effective components. Peripheral (which lowers blood pressure) effects are blocked by N-methylscopolamine, so that only the central (which raises blood pressure) effect of arecoline occurs. This central effect is blocked by brain precursor antimuscarinics.

Method:

Single rats weighing 300 g are anesthetized with urethane (1.2 g/kg) i.p. The trachea is incubated, the animals are given artificial respiration with a mixture of air and oxygen (80 breaths per minute). Blood pressure is recorded after cannulation of the A. carotis using a pressure recorder (Bell and Howell, type 4-327-I). Test substances are applied via the jugular vein (0.5 mol/kg). Before the start of the experiment, the animals received 0.5 mg/kg of N-methyl-scopolamine. Arecoline is applied (0.3 mg/kg each time) 15 minutes apart. After 2 comparative values, each time before re-application of arecoline, the test substance is injected with increasing dosage.

The achieved results are compared with the average initial values and the % inhibition is determined. The values obtained from the test with arecoline are listed in Table 2.

C) Effect on memory in the Morris water maze

The research is carried out using the water maze described by R.G.M. Morris in Learn Motive 12, 239-249 (1981) for the experimental design described there.

24-month-old rats with learning disabilities (n = 7/group) received 0.2 mg/kg of compound D subcutaneously on day 1, the second group of these animals received a saline solution (s.c.). The groups are observed for 4 days in the Morris water maze.

From the course of the obtained curves shown in Figure 1, it can be seen that the administration of compound S causes an improved memory ability of the animals compared to the animals that received only the physiological saline solution, and in which age impairs learning. Thus, for example, on the second day, the latent time is reduced by approximately 50%. In 4 days, the animals treated with substance D reach the same level as the control animals of the group of young rats (n = 7/group), which received only physiological saline solution. This effect of the M2-antagonist according to the invention is surprising, because for the M2-selective antagonist pirenzepine, weaker learning abilities and memory abilities have been observed (A.J. Hunter and F.F. Roberts, Pharmacol. Biochem. in Behavior Vol. 30, 519523 (1988), title: " The effects of pirenzepine on spatial learning in the Morris Water Maze"). About similar negative observations with selective substances, such as scopolamine or atropine; also written by A.J. Hunter, F.F. Roberts and C.A. Tutty in Br. J. Pharmacol. 87, 41P, 1986; R.J. Sutherland, I.Q. Wishaw and J.C. Regehr, J. Comp. Physiol. Psysiol. Psychol. 96, 563-573 (1982) and Wihaw, Behav. Neuroscientists. 99, 979-1005 (1985).

In accordance with the above versions, we tested the following compounds:

A=5,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxobutyl]ethyl-mino]-propyl-1-piperidinyl]acetyl-6H-pyrido[2,3- b]-[1,4-benzodiazepine-6-one,

B=5,11-dihydro-[[4-[3-[(2,2-dimethyl-1-oxopentyl]ethyl-amino]-propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b ]-[1,4-benzodiazepine-6-one,

C=5,11-dihydro-11-[[4-[4-[(2,2-dimethyl-1-oxopentyl]ethyl-amino]-butyl-1-piperidinyl]acetyl]-6H-pyrido[2,3 -b]-[1,4-benzodiazepine-6-one,

D=5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1oxopentyl]ethyl-amino]-propyl-1-piperidinyl]acetyl]-6H-pyrido[2 , 3-b]-[1,4-benzodiazepine-6-one,

E=5,11-dihydro-8-methyl-11-[[4-[3-[(2,2-dimethyl-oxopropyl]ethyl-amino]-propyl-1-piperidinyl]acetyl]-6H-pyrido [2 ,3-b]-[1,4-benzodiazepine-6-one,

F=5,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxopropyl]ethylamino]-propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b ]-[1,4-benzodiazepine-6-one,

G=5,11-dihydro-8-methyl-11-[[4-[3-[(2,2-dimethyl-1-oxobutyl]ethylamino]-propyl-1-piperidinyl]acetyl]-6H-pyrido [2 ,3-b]-[1,4]benzodiazepine-6-one,

and compared with the following substances:

H=11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one (see USPS No. 4,550,107),

I=11-[[4-[4-(diethylamino)butyl)-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one (see EP-A2-0 312 895),

from EP-A1-= 402 734:

J = 5,11-dihydro-11-[1-oxo-6-(1-piperidinyl)-4-hexyl-1-yl]-6H-pyrido[2,3-b][1, 4]benzodiazepine-6 -he,

K=(+)-9-chloro-11-[[2-[(diethylamino)methyl]-1-piperidinyl]-acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1, 4] benzodiazepine-6-one,

L=5,11-dihydro-11-[[[2-[2-[(dipropylamino)methyl]-1-piperidinyl]ethyl]amino]carbonyl]-6H-pyrido[2,3-b][1,4 ] benzodiazepine-6-one-methanesulfonate,

M=5,11-dihydro-11-[[3-[3-(1-piperidinyl)-1-propyl]-1-piperidinyl]carbonyl]-6H-pyrido[2,3-b]-[1,4 ] benzodiazepine-6-one,

N=4,9-dihydro-3-methyl-4-[[4-][3-(1-piperidinyl)-1-propyl]-1-piperidinyl]acetyl]-10H-thieno[2,3-b] -[1,5] benzodiazepine-10-one,

O = 5,11-dihydro-11-[1-oxo-6-(1-piperidinyl)-1-hexyl)-1-6H-pyrido[2,3-b]-[1,4]benzodiazepine-6- he,

P=4,9-dihydro-3-methyl-4-[6-hexahydro-1H-1-azepinyl)-1-oxo-4-hexyl-1-yl]-10H-thieno[3,4-b]- [1,5] benzodiazepine-10-one,

Q=11-[4-[3-(diethylamino)methyl]-4-morpholinyl]-1-oxo-1-butyl]-5,11-dihydro-6H-pyrido[2,3-b]-[1, 4] benzodiazepine-10-one,

R=5,11-dihydro-11-[[[2-(1-methyl-2-pyrrolidinyl)ethyl]methyl-amino]acetyl-6H-pyrido[2,3-b][1,5]benzodiazepine-10 -he,

S=5,11-dihydro-11-[[[2-(1-methyl-2-hexahydro-1H-2-azepinyl)-ethyl]-methylamino]acetyl-6H-pyrido[2,3-b]-[ 1,5] benzodiazepine-10-one.

The results are listed in the following tables 1 and 2.

Table 1

In vitro receptor binding assay

The results:

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Table 2

Penetration of the central nervous system in vitro (rat)

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As can be seen from Table 1, the listed compounds from A to G show outstanding M1/M2 selectivity in the 10-35 range. This ratio means that the mentioned compounds are highly M2-selective and therefore can block presynaptic M2-receptors in the brain, in the range of doses in which there is no effect on M1-receptors. In contrast, comparators H to S show only moderate M1/M2 selectivity with a selectivity ratio below 6.6. A comparison of these selectivity values shows that the new diazepinones of the general formula I strongly outperform the comparative substances.

The main assumption for the usability of compounds for the treatment of diseases of the central nervous system is the brain transitivity of the substance. The previously described experimental model to demonstrate penetration of the central nervous system clearly shows (see Table 2) that substances A to G are capable of inhibiting arecoline-mediated central effects. This fact can only be explained on the basis of good transitivity of the central nervous system. In contrast, the tested comparative substances H, K, Z and O with ED50 values above 10 mg/kg (i.v.) do not act on arecoline-mediated blood pressure increase. This clearly proves that these compounds show significantly weaker penetration into the central nervous system.

The following examples illustrate the invention.

Example 1

5,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxobutyl]ethylamino]-propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b]- [1,4]

-benzodiazepine-6-one

1.48 g (0.01 mol) of 2,2-dimethylbutyric acid chloride dissolved in 20 ml of tetrahydrofuran is added dropwise with stirring at room temperature to a solution of 4.2 g (0.01 mol) of 5,11-dihydro-11- [[4-(3-Ethylamino)propyl-1-piperidinyl]-acetyl]-6H-pyrido[2,3-b]-[1,4]-benzodiazepine-6-one in 2 ml of triethylamine in 150 ml of tetrahydrofuran. To complete the reaction, the solution is stirred for another 1 hour at 50°C. After cooling, the secreted triethylamine hydrochloride is separated by filtration and the filtrate is evaporated to dryness on a rotary evaporator under the vacuum of a water pump. For cleaning, the residue is dissolved in ethyl acetic acid. The solution in ethyl acetic acid is shaken twice with 10% hydrochloric acid, the organic phase is separated and the aqueous phase is made alkaline by adding concentrated ammonia. The aqueous phase is then extracted twice with ethyl acetic acid. The organic phase is dried over sodium sulfate and evaporated to dryness under vacuum. The resulting residue crystallizes by digesting in ethyl acetic acid. Benzocolor crystals with a melting point of 136-138°C are obtained.

Yield: 2.4 g (46.2% of theoretical).

Example 2

5,11-dihydro-11-[[4-(3-[(benzoyl)-ethylamino]-propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6

-ondihydrochloride

Prepared analogously to Example 1 from 5,11-dihydro-11-[[4-[3-[ethylamino]-propyl-1-piperidinyl]acetyl]-6H-pyrido] [2,3-b]-[1,4] benzodiazepine-6-one and benzoic acid chloride. The free base is dissolved in acetic acid ethyl ester and the dihydrochloride is precipitated by adding ethereal hydrochloric acid. Recrystallization from ethanol gives the desired compound with a yield of 62%.

Colorless crystals with a melting point of 152-154°C (ethanol).

Example 3

5,11-dihydro-11-[[4-[3-[(methoxybenzoyl)ethylamino]-propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4] benzodiazepine-6- ondihydrochloride

Prepared analogously to example 1 from 5,11-dihydro-11-[[4-[3-[(ethylamino)-propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b]-[1,4] benzodiazepine-6-one and 4-methoxybenzoic acid chloride. The free base is dissolved in acetic acid ethyl ester and the dihydrochloride is precipitated by adding ethereal hydrochloric acid. Recrystallization from ethanol gives the desired compound with a yield of 81%.

Colorless crystals with a melting point of 163-165°C (ethanol).

Example 4

5,11-dihydro-11-[[4-[3-[(3,4-dimethoxybenzoyl)-ethylamino]-propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4 ]

benzo-di-azepin-6-one

Prepared analogously to example 1 from 5,11-dihydro-11-[[4-[3-[(ethylamino]-propyl]-1-piperidinyl]acetyl]-6H-pyrido [2,3-b]-[1,4 ]benzodiazepine-6-one and 3,4-dimethoxybenzoic acid chloride The free base is dissolved in ethyl acetic acid and the dihydrochloride is precipitated by the addition of ethereal hydrochloric acid.

Utilization: 78% of the theoretical.

Colorless crystals with a melting point of 160-162°C (ethanol).

Example 5

5,11-dihydro-11-[[4-[3-((phenylacetyl)ethylamino]-propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine

-6-one-dihydrochloride

Prepared analogously to example 1 from 5,11-dihydro-11-[[4-[3-[(ethylamino]-propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4] benzodiazepine-6-one and phenylacetyl chloride chloride The free base is purified by chromatography on silica gel (Merck company. 30-60 µn) with a mixture of ethyl acetate and methanol (98:2) as eluent and then treated with ethereal hydrochloric acid translate dihydrochloride.

Utilization: 24% of the theoretical.

Colorless crystals with a melting point of 149-152°C (ethanol).

Example 6

5,11-dihydro-11-[[4-[3-[(acetyl)ethylamino]-propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6- he

Prepared analogously to example 1 from 5,11-dihydro-11-[[4-[3-[(ethylamino)-propyl]-1-piperidinyl]acetyl]-6H-pyrido [2,3-b]-[1,4 ]benzodiazepine-6-one and acetyl chloride with a utilization of 56% of the theoretical.

Colorless crystals with a melting point of 178-180°C (acetic acid ethyl ester).

Example 7

5,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxopropyl)ethylamino]-propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][ 1,4] benzo-di-azepin-6-one

Prepared analogously to example 1 from 5,12-dihydro-11-[[4-[3-[(ethylamino]propyl)-1-piperidinyl]acetyl]-6H-pyrido [2,3-b]-[1,4] of benzodiazepine-6-one and pivalic acid chloride with a recovery of 61% of the theoretical.

Colorless crystals with a melting point of 154-155°C (acetic acid ethyl ester).

Example 8

5,11-dihydro-11-[[2-[2-(benzoyl)methylamino]ethyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one

A mixture of 9.5 g (0.033 mol) 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one, 9.8 g (0, 04 mol) of 2-[2-(benzoyl)methylamino]ethyl-1-piperidine, 4.2 g (0.04 mol) of sodium carbonate and 300 ml of acetonitrile are heated under reflux for 10 hours. The reaction mixture is then filtered and the filtrate is evaporated to dryness under vacuum. The obtained crude product was purified by chromatography on silica gel (Raker company, 30-60 µm) and with a mixture of methylene chloride/methanol/cyclohexane/ammonia/acetic ester = 68:15:15:2:500 as eluent.

Colorless crystals with a melting point of 115-130°C.

Yield: 3.8 g (28% of theoretical).

Example 9

5,11-dihydro-11-[[4-[3-[2,2-dimethyl-1-oxo-pentyl]ethylamino]-propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b ][1,4] benzo-di-azepin-6-one

Prepared analogously to example 1 from 5,11-dihydro-11-[[4-[3-[(ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido [2,3-b]-[1,4] of benzodiazepine-6-one and 2,2-dimethylvaleric acid chloride with a yield of 62% of the theoretical.

Colorless crystals with a melting point of 138-140°C (diethyl ether).

Example 10

5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxopropyl]-ethylamino]propyl-1-piperidinyl]acetyl]-6H-pyrido

[2,3-b]-[1,4]benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-8-chloro-11-[[4-[3-[(ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1 ,4]benzodiazepine-6-one and pivalic acid chloride with a recovery of 77% of the theoretical.

Colorless crystals with a melting point of 168-170°C (acetic acid ethyl ester).

Example 11

5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxobutyl)-ethylamino]propyl-1-piperidinyl]acetyl]-6H-pyrido

[2,3-b][l, 4]-benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-8-chloro-11-[[4-[3-[(ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1 ,4]-benzodiazepine-6-one and 2,2-dimethyl-butyric acid chloride with a yield of 36% of the theoretical.

Colorless crystals with a melting point of 173-174°C (diisopropylether).

Example 12

5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxopentyl)-ethylamino]propyl-1-piperidinyl]acetyl]-6H-pyrido

[2,3-b][1,4]-benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-8-chloro-11-[[4-[3-[(ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1 ,4]benzodiazepine-6-one and 2,2-dimethyl-valeric acid chloride with a utilization of 70% of the theoretical.

Colorless crystals with a melting point of 172-173°C (acetic acid ethyl ester).

Example 13

5,11-dihydro-8-chloro-11-[[4-[3-[(cyclopropylcarbonyl)ethyl-amino]propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4 ]

-benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-8-chloro-11-[[4-[3-[(ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1 , 4]benzodiazepine-6-one and cyclopropane-carboxylic acid chloride with a yield of 76% of the theoretical.

Colorless crystals with a melting point of 136-138°C (diethyl ether/ethyl ester of acetic acid).

Example 14

5,11-dihydro-8-methyl-11-[[4-[3-[(2,2-dimethyl-1-oxopropyl)-ethylamino]propyl-1-piperidinyl]acetyl]-6H-pyrido

[2,3-b][1,4]-benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-8-methyl-11-[[4-[3-[(ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1 ,4]benzodiazepine-6-one and pivalic acid chloride with a yield of 23% of the theoretical.

Colorless crystals with a melting point of 177-179°C (acetonitrile).

Example 15

5,11-dihydro-9-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxopentyl)-ethylamino]propyl-1-piperidinyl]acetyl]-6H-pyrido

[2,3-b]-[1,4]benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-9-chloro-11-[[4-[3-[(ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][l ,4]benzodiazepine-6-one and 2,2-dimethyl-valeric acid chloride Purified by chromatography on silica gel (Merck, 30-60 µm) with a mixture of ethyl acetate/ammonia (10:0.1) as eluent for rinsing.Utilization 48% of the theoretical.

Colorless crystals with a melting point of 150-152°C (diethyl ester).

Example 16

5,11-dihydro-9-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxobutyl)-ethylamino]propyl-1-piperidinyl]acetyl]-6H-pyrido

[2,3-b][1,4]-benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-9-chloro-11-[[4-[3-[(ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1 ,4]benzodiazepine-6-one and 2,2-dimethylbutyric acid chloride The base was purified by chromatography on silica gel (Merck, 30-60 µm) with a mixture of ethyl acetate/ammonia (10:0.1) as eluent. rinse.

Utilization 54% of the theoretical.

Colorless crystals with a melting point of 123-125°C (diethyl ether).

Example 17

5,11-dihydro-8-methyl-11-[[4-[3-[(2,2-dimethyl-1-oxobutyl)-ethylamino]propyl-1-piperidinyl]acetyl]-6H-pyrido

[2,3-b][1,4]benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-8-methyl-11-[[4-[3-[(ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1 . for rinsing.

Utilization 41% of the theoretical.

Colorless crystals with a melting point of 97-99°C (acetic acid ethyl ester).

Example 18

5,11-dihydro-8-methyl-11-[[4-[3-[(2,2-dimethyl-1-oxopentyl)-ethylamino]propyl-1-piperidinyl]acetyl]-6H-pyrido

[2,3-b][1,4]-benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-8-methyl-11-[[4-[3-[(ethylamino]propyl)-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1 ,4]benzodiazepine-6-one and 2,2-dimethyl-valeric acid chloride. It is purified by chromatography on silica gel (Baker company, 30-60 µm) with a mixture of ethyl acetic acid/ammonia (10:0.1) as eluent.

Utilization 28% of the theoretical.

Colorless crystals with a melting point of 83-85°C (acetic acid ethyl ester).

Example 19

5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxo-4-penten-1-yl)ethylamino]propyl-1-piperidinyl]acetyl]- 6H-pyrido[2,3-b][1,4]benzodiazepine-6-one

Prepared analogously to example 1 from 2,2-dimethyl-4-pentenoic acid chloride and 5,11-dihydro-8-chloro-11-[[4-[3-[(ethylamino]propyl]-1-piperidinyl]acetyl]- 6H-pyrido[2,3-b]-[1,4]benzodiazepine-6-one Purified by chromatography on silica gel (Baker, 30-60 µm) with a mixture of ethyl acetate/methanol/cyclohexane/ammonia (8 :1:1:0,1) as a rinsing agent.

Utilization 88% of the theoretical.

Colorless crystals with a melting point of 157-158°C (diethyl ether).

Example 20

5,11-dihydro-8-chloro-11-[[4-[3-[(cyclohexylcarbonyl)-ethyl-amino]propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b]

[1,4]benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-8-chloro-11-[[4-[3-[(ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1 ,4]benzodiazepine-6-one and cyclohexanecarboxylic acid chloride Purified by chromatography on silica gel (Baker, 30-60 µm) with a mixture of ethyl acetic acid/methanol/cyclohexane/ammonia (8:1.1:0.1) as an eluent for rinsing.

Utilization 70% of the theoretical.

Colorless crystals with a melting point of 162-163°C (diethyl ether).

Example 21

5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxopentyl)-ethylamino]propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3 -b] [1,4]-benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-8-chloro-11-[[4-[3-[(ethylamino]propyl)-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1 ,4]benzodiazepine-6-one and valerian acid chloride. It is purified by chromatography on silica gel (Baker company, 30-60 µm) with a mixture of ethyl ester of acetic acid/methanol/cyclohexane/ammonia (8:1.1:0.1) as eluent.

Utilization 73% of the theoretical.

Colorless crystals with a melting point of 150-520°C (diethyl ether).

Example 22

5,11-dihydro-8-chloro-11-[[4-[3-[(1-oxobutyl)ethylamino]propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4 ]

benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-8-chloro-11-[[4-[3-[(ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1 ,4]benzodiazepine-6-one and butyric acid chloride Purification by chromatography on silica gel analogous to example 21.

Utilization 75% of the theoretical.

Colorless crystals with a melting point of 152-154°C (diethyl ether).

Example 23

5,11-dihydro-8-chloro-11-[[4-[3-[(1-oxopropyl)ethylamino]-propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1, 4]

benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-8-chloro-11-[[4-[3-[(ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1 ,4]benzodiazepine-6-one and propionic acid chloride Purification by chromatography on silica gel analogous to example 21.

Utilization 77% of the theoretical.

Colorless crystals with a melting point of 141-143°C (diethyl ether).

Example 24

5,11-dihydro-8-chloro-11-[[4-[3-[(1-oxopropyl)ethylamino]-propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1, 4]

benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-11-[[4-[3-[(ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido [2,3-b][1,4]benzodiazepine -6-one and propionic acid chloride Purification by chromatography on silica gel analogous to example 21.

Utilization 50% of the theoretical.

Colorless crystals with a melting point of 123-125°C (diethyl ether).

Example 25

5,11-dihydro-11-[[4-[3-[(1-oxobutyl)ethylamino]propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine

-6-he

Prepared analogously to example 1 from 5,11-dihydro-11-[[4-[3-[(ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine -6-one and butyric acid chloride Purification by chromatography on silica gel analogous to example 21.

Utilization 61% of the theoretical.

Colorless crystals with a melting point of 174-175°C (diethyl ether).

Example 26

5,11-dihydro-11-[[4-[3-[(1-oxopentyl)ethylamino]propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine

-6-he

Prepared analogously to example 1 from 5,11-dihydro-11-[[4-[3-[(ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine -6-one and valerian acid chloride Purification by chromatography on silica gel analogous to example 21.

Utilization 77% of the theoretical.

Colorless crystals with a melting point of 167-168°C (diethyl ether).

Example 27

5,11-dihydro-8-chloro-11-[[4-[3-[(1-methylcyclohexylcarbonyl)-ethylamino]propyl-1-piperidinyl]acetyl]-6H-pyrido

[2,3-b][1,4]benzodiazepine-6-one

A solution of 313 mg (2.2 mmol) of 1-methylcyclohexane-carboxylic acid and 340 mg (3.0 mmol) of N,N'-carbonyl-diimidazole in 20 ml of tetrahydrofuran is heated with stirring for 1 hour at 45°C. Then 920 mg (2 mmol) of 5, 11-dihydro-8-chloro-[[4-[3-[(ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b] is added [1,4]benzodiazepine-6-one and the reaction mixture are stirred for another 2 hours at 45° C. After the completion of the reaction, the reaction mixture is poured into a saturated sodium chloride solution, the organic phase is separated and evaporated to dryness under vacuum. partition between water and ethyl acetate and the phase in ethyl acetate is then evaporated in vacuo. The crude product obtained is purified by chromatography on silica gel (Baker, 30-60 µm) with a mixture of ethyl acetate/methanol/ammonia (9:1 :0.1).The desired compound is obtained as an amorphous product with a yield of 130 mg (11% of the theoretical.

Rf value in thin-layer chromatogram: 0.4 (plates CD: silica gel from Merck; eluent: methylene chloride/cyclohexane/methanol/ammonia = 680:150:150:20).

Example 28

5,11-dihydro-8-chloro-11-[[4-[3-[(tricyclo[3,3,1,13,7]dec-1-yl-carbonyl)ethylamino]propyl-1-piperidinyl]acetyl ]-6H-pyrido-[2,3-b][1,4]benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-8-chloro-11-[[4-[3-[(ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1 ,4]benzodiazepine-6-one and tricyclo-[3,3,1,13,7]decane-1-carboxylic acid chloride with a yield of 20% of the theoretical Purification by chromatography on silica gel (Baker company, 30-60 µm) with a mixture of ethyl acetate/cyclohexane/methanol/ammonia (80:10:10:1) as eluent.

Rf value in thin layer chromatogram: 0.65 (plates CD: silica gel from Merck; eluent: methylene chloride/cyclohexane/methanol/ammonia = 680:150:150:20).

Example 29

5,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxopropyl)-ethyl-amino]butyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b ][1.4]

-benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-11-[[4-[3-[(ethylamino]butyl]-1-piperidinyl]acetyl]-5H-pyrido[2,3-b]-[1,4] benzodiazepine-6-one and pivalic acid chloride with a yield of 62% of the theoretical.

Colorless crystals with a melting point of 206-207°C (acetic acid ethyl ester).

Example 30

5,11-dihydro-11-[[4-[4-[(cyclopropylcarbonyl)-ethylamino]-butyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]

benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-11-[[4-[4-[(ethylamino]butyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b]-[1,4] benzodiazepine-6-one and cyclopropanecarboxylic acid chloride with a yield of 67% of the theoretical.

Colorless crystals with a melting point of 202-204°C (acetic acid ethyl ester).

Example 31

5,11-dihydro-11-[[4-[(2,2-dimethyl-1-oxobutyl)ethylamino]-butyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4 ]

benzodi-azepin-6-one

Prepared analogously to example 1 from 5,11-dihydro-11-[[4-[4-[(ethylamino]butyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b]-[1,4] benzodiazepine-6-one and 2,2-dimethylbutyric acid chloride with a yield of 64% of the theoretical.

Colorless crystals with a melting point of 153-155°C (diethyl ether).

Example 32

5,11-dihydro-11-[[4-[(2,2-dimethyl-1-oxopentyl)ethylamino]-butyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4 ]

benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-11-[[4-[4-[(ethylamino]butyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine -6-one and 2,2-dimethylvaleric acid chloride with a yield of 69% of the theoretical.

Colorless crystals with a melting point of 168-169°C (acetic acid ethyl ester).

Example 33

5,11-dihydro-11-[[4-[(3,4-dimethoxybenzoyl)ethylamino]butyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]

benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-11-[[4-[4-[(ethylamino]butyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine -6-one and chloride of 3,4-dimethoxybenzoic acid with a yield of 67% of the theoretical.

Colorless crystals with a melting point of 132-135°C (acetic acid ethyl ester).

Example 34

5,11-dihydro-8-chloro-11-[[4-[(2,2-dimethyl-1-oxo-propyl)-ethylamino]butyl-1-piperidinyl]acetyl]-6H-pyrido[2,3- b]

[1,4]benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-8-chloro-11-[[4-[4-[(ethylamino]butyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1 ,4]benzodiazepine-6-one and pivalic acid chloride with a yield of 55% of the theoretical.

Colorless crystals with a melting point of 205-207°C (acetic acid ethyl ester).

Example 35

5,11-dihydro-8-chloro-11-[[4-[(2,2-dimethyl-1-oxo-pentyl)-ethylamino]butyl-1-piperidinyl]acetyl]-6H-pyrido[2,3- b]

[1,4]benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-8-chloro-11-[[4-[4-[(ethylamino]butyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1 ,4]benzodiazepine-6-one and 2, 2-dimethylvaric acid chloride with a yield of 60% of the theoretical:

Colorless crystals with a melting point of 149-151°C (acetic acid ethyl ester).

Example 36

4,9-dihydro-3-methyl-[[4-[(3-2,2-dimethyl-1-oxobutyl)-ethylamino]propyl-1-piperidinyl]acetyl]-10H-thieno-[3,4-b ]

[1,4]benzodiazepine-10-one

Prepared analogously to example 1 from 4,9-dihydro-3-methyl-4-[[4-[3-[(ethylamino]propyl]-1-piperidinyl]acetyl]-10H-thieno[3,4-b][l ,5]benzodiazepine-10-one and 2,2-dimethylbutyric acid chloride with a yield of 19% of the theoretical.

Colorless crystals with a melting point of 207-208°C (acetonitrile).

Example 37

4,9-dihydro-3-methyl-[[4-[4-3[2,2-dimethyl-1-oxopropyl)-ethylamino]propyl-1-piperidinyl]acetyl]-10H-thieno-[3,4- b]

[1,4]benzodiazepine-6-one

Prepared analogously to example 1 from 4,9-dihydro-3-methyl-4-[[4-[3-[(ethylamino)propyl]-1-piperidinyl]acetyl]-10H-thieno[3,4-b][1 ,5]benzodiazepine-10-one and pivalic acid chloride with a yield of 29% of the theoretical.

Colorless crystals with a melting point of 188-189°C (acetonitrile).

Example 38

5,11-dihydro-11-[[4-[2-(benzoyl)methylamino]ethyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-11-[[4-[2-[(methylamino)ethyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine -6-one and benzoyl chloride with a yield of 80% of the theoretical.

Colorless crystals with a melting point of 120-122°C (acetic acid ethyl ester).

Example 39

5,11-dihydro-11-[[4-[[(acetyl)methylamino]methyl-1-piperidinyl]-acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one

Prepared analogously to example 1 from 5,11-dihydro-11-[[4-[-(methylamino]methyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6 -one and acetyl chloride with a utilization of 83% of the theoretical.

Colorless crystals with a melting point of 242-243°C (acetic acid ethyl ester).

Example 40

3-chloro-4-[[4-[3-[(2,2-dimethyl-1-oxopropyl)methylamino]propyl]-1-piperidinyl]acetyl]-1-methyl-1,4,9,10-tetrahydro

-pyrrolo-[2,3-b][1,5]benzodiazepine-6-one

Prepared analogously to example 1 from 3-chloro-4-[[4-[3-[(ethylamino]propyl)-1-piperidinyl]acetyl-1-methyl-1,4,9,10-tetrahydropyrrolo[3,2-b ][1,5]benzodiazepine-10-one and pivalic acid chloride with a yield of 42% of the theoretical.

Colorless crystals with a melting point of 150-151°C (acetic acid ethyl ester).

Example 41

6,11-dihydrop-11-[[4-[3-[(2,2-dimethyl-1-oxopentyl)ethylamino)-propyl-1-piperidinyl]acetyl]-1-methyl-5H-pyrido[2,3 -b][1,5]benzodiazepine-6-one

Prepared analogously to example 1 from 6,11-dihydro-11-[[4[3-[(ethylamino)propyl-1-piperidinyl]acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepine-6 -one and chloride of 2,2-dimethylvaleric acid with a yield of 44% of the theoretical.

The value of Rf. in a thin-layer chromatogram: (plates DC: silica gel from Merck; eluent: methylene chloride/cyclohexane/methanol/ammonia = 6, 8:1, 5:1, 5:0.2).

Example 42

5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxopentyl)-ethylamino]propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3 -b-1,4]benzodiazepine-6-one

To a solution of 0.52 g [4 mmol] of 2,2-dimethylvaleric acid and 0.54 g (4 mmol) of 1-hydroxybenzotriazole in 50 ml of tetrahydrofuran is added at 0°C with stirring 0.82 g (4 mmol) of N ,N'-dicyclohexylcarbodiimide. It is stirred for another 30 minutes at the same temperature and then 1.8 g (4 mmol) of 5,11-dihydro-8-chloro-11-[[4-[3-[(ethylamino) propyl]-1-piperidinyl] is added. acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one. It is then stirred for another 12 hours at room temperature. The resulting dicyclohexylurea is filtered off with suction and the filtrate is evaporated to dryness under vacuum. The residue was purified on silica gel (Baker) with a mixture of ethyl acetic acid/methanol/cyclohexane/ammonia = 8:1:1:0.1 as eluent. Colorless crystals with a melting point of 172-173°C (ethyl acetic acid) are obtained.

Utilization. 160 mg = 7% of the theoretical.

According to its physicochemical and spectroscopic data, this substance is completely identical to the substance obtained in example 12.

Example 43

5,11-dihydro-11-[[3-[3-[(benzoyl)methylamino]propyl-1-piperidinyl]acetyl]-6H-pyrida[2,3-b][1,4]benzodiazepine-6

-he

Prepared analogously to example 8 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one and

3-[3[(benzoyl)methylamino]propyl]piperidine. Cleaning is carried out on silica gel with a mixture of methylene chloride/methanol = 99:1 as a washing agent.

Utilization: 43% of the theoretical.

Colorless crystals with a melting point of 172-173°C.

Example 44

5,11-dihydro-11-[[3-[3-[(acetyl)methylamino]propyl-1piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one

Prepared analogously to example 8 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one and 3-[3[(acetyl)methylamino]propyl] piperidine. Purification is carried out on silica gel (Baker) with methylene chloride to which increasing amounts of methanol are added.

Utilization: 23% of the theoretical.

Colorless crystals with a melting point of 170-172°C.

Example 45

5,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxopentyl)amino]propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1 ,4]

benzodi-azepin-6-one

Prepared analogously to example 1 from 5,11-dihydro-11-[[4-[3-(aminopropyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6- it and 2,2-dimethylvaleric acid chloride with a yield of 64% of the theoretical.

Colorless crystals with a melting point of 150-152°C (acetic acid ethyl ester).

Example 46

5,10-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxopentyl)-propyl]-1-piperidinyl]acetyl]-11H-dibenzo[b,e][1,4 ]diazepine

-6-he

Prepared analogously to example 1 from 5,10-dihydro-5-[[4-[3-ethylamino]propyl]-1-piperidinyl]acetyl]-11H-dibenzo[b,e]-[1,4]diazepine-6- she.

It is purified by chromatography on silica gel (Merck company, 30-60 µm) with a mixture of ethyl acetic acid/ammonia (10:0.1) as eluent.

Utilization 53% of the theoretical.

Colorless crystals with a melting point of 124-126°C (diethyl ether).

Rf value in thin layer chromatogram: 0.5 (plates DC: silica gel from Merck; eluent: methylene chloride/cyclohexane/methanol/ammonia = 6.8:1.5:1.5:0.2.

Several examples of the preparation of pharmaceutical dosage forms are described below.

Examples

Tablets with 5 mg 5,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxo-butyl)ethylamino]propyl-1-piperidinyl]acetyl]-6H

-pyrido[2,3-b]-[1, 4]benzodiazepine-6-one

Composition:

1 tablet contains

active substance 5.0 mg

milk sugar 148.0 mg

potato starch 65.0 mg

magnesium stearate 2.0 mg

220.0 mg

Preparation process

A 10% slime is prepared from potato starch by heating. The active substance, milk sugar and the remaining potato starch are mixed with the upper mucus, granulated through a sieve with a mesh width of 1.5 mm. The granulate is dried at 45°C, sieved through the top sieve once more, mixed with magnesium stearate and crushed into tablets.

Tablet mass 220 mg.

Diameter: 9 mm.

Example II

Dragees with 5 mg of 5,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxo-butyl)ethylamino]propyl-1-piperidinyl]acetyl]-6H

-pyrido[2,3-b]-[1,4]-benzodiazepine-6-one

Tablets prepared according to Example 1 are coated with a coating consisting mainly of sugar and talc. Finished dragees are polished using beeswax.

The mass of the dragee is 300 mg.

Example III

Ampoules with 10 mg with 5 mg 5,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxopentyl]ethylamino]propyl-1-piperidinyl]acetyl]

-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one

Composition:

1 ampoule contains

active substance 10.0 mg

sodium chloride 5.0 mg

dest. water ad 1 ml

Preparation process

The active substance and sodium chloride are dissolved in distilled water and then topped up to the specified volume. The solution is sterile filtered and filled into ampoules with a volume of 1 ml.

Sterilization: 20 minutes at 120°C.

Example IV

Suppositories with 20 mg of 5, 11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxopentyl)ethyl-amino]-propyl-1-piperidinyl]acetyl]

-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one

Composition:

1 suppository contains

active substance 20.0 mg

weight of the suppository (eg Witepsol W 45®) 1680.0 mg

1700, 0 mg

Preparation process

The active substance crushed into a fine dust is suspended in the melt of the suppository mass cooled to 40°C. The mass is poured at 37°C into pre-cooled molds for suppositories.

Weight of the suppository: 1.7 g.

Example V

Drops with 5,11-dihydro-11-[[4-[4-[(2,2-dimethyl)-1-oxopentyl]ethylamino]butyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b ][1,4]-benzodiazepine-6-one

Composition:

100 ml of drops solution contains:

p-hydroxybenzoic acid methyl ester 0.035 g

p-hydroxybenzoic acid propyl ester 0.015 g

anise oil 0.05 g

menthol 0.06 g

pure ethanol 10.0 g

active substance 0.5 g

sodium cyclamate 1.0 g

glycerin 15.0 g

distilled water ad 100 ml

Preparation process

The active substance and sodium cyclamate are dissolved in approximately 70 ml of water and glycerin is added. The ester of p-hydroxybenzoic acid, aniseed oil and methanol are dissolved in ether and this solution is added to the aqueous solution. At the end, it is topped up with water to 100 ml and filtered so that there are no floating particles.

Claims (9)

1. Condensed diazepinones of general formula I [image] indicated by that B represents one of the divalent states [image] and X, 1, m, n and R1 to R7 have the following meanings: X is the group =CH or, if B represents a divalent residue (S), also a nitrogen atom; 1 is an integer of 1, 2 or 3; m is an integer of 1 or 2; n is an integer of 1, 2, 3 or 4; R1 represents a hydrogen atom or a straight or branched alkyl group with 1 to 6 carbon atoms; R2 represents a hydrogen atom, a straight or branched alkyl group with 1 to 8 carbon atoms, a straight or branched alkenyl group with 4 to 6 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, in a given case substituted with an alkyl group having 1 to 3 carbon atoms, an adamantyl group, a phenyl group, in a given case substituted with one or two methyl or methoxy groups or a halogen atom, or a phenylalkyl group with 1 to 3 carbon atoms in the alkyl part, in a given case substituted on the aromatic with a methyl or methoxy group or by a halogen atom; R3 and R4, which may be the same or mutually different, represent hydrogen or halogen atoms or methyl, ethyl, methoxy or ethoxy groups; R5 represents a hydrogen or chlorine atom or a methyl group; R6 and R7, which can be the same or mutually different, represent hydrogen atoms or alkyl groups with 1 to 3 carbon atoms, and R7 can additionally also represent a halogen atom, and their salts with inorganic or organic acids. 2. Condensed diazepinones of the general formula I according to claim 1, characterized in that X is a nitrogen atom, B is a divalent residue (S), 1 is number 2, m is the number 1, n represents the numbers 3 and 4, R1 is a straight alkyl group with 1 to 4 carbon atoms, R2 is a branched alkyl group with 4 to 6 carbon atoms, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclopentyl, methyl-cyclohexyl, methylcycloheptyl or adamantyl group, R3 and R4 represent hydrogen atoms or one of these residues represents a methyl group or a halogen atom and the substituent - (CH2)n-NR1-CO-R2 is connected to position 4 of the piperidinyl ring, and their salts and inorganic or organic acids. 3. Condensed diazepinones of the general formula I according to claim 2, characterized in that R1 represents an ethyl group, and their salts with inorganic or organic acids. 4. The following compounds of the general formula I according to claim 2, characterized in that they are 5,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxobutyl]ethyl-amino]propyl]-1-piperidinyl] acetyl]-6H-pyrido [2,3-b ]-[1,4]- benzodiazepine-6-one; 5,11-dihydro-[[4-[3-f(2/2-dimethyl-1-oxopentyl]ethyl-amino]-propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b] -[14]-benzodiazepine-6-one; 5,11-dihydro-11-[[4-[4-[(2,2-dimethyl-1-oxopentyl]ethyl-amino]-butyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b ]-[1,4J-benzodiazepine-6-one; 5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxo-pentyl]ethylamino]-propyl-1-piperidinyl]acetyl]-6H-pyrido[2 ,3-b]-[1,4]-benzodiazepine-6-one; 5,11-dihydro-8-methyl-11-[[4-[3-[(2,2-dimethyl-1-oxopropyl]ethyl-amino]-propyl-1-piperidinyl]acetyl]-6H-pyrido[2 ,3-b-[1,4]-benzodiazepine-6-one; 5,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxopropyl]ethyl-amino]-propyl-1-piperidinyl]acetyl]-6H-pyrido[2,3-b ]-[1,4]-benzodiazepine-6-one and 5,11-dihydro-8-methyl-11-[[4-[3-[(2,2-dimethyl-1-oxo-butyl]ethyl-amino]-propyl-1-piperidinyl]acetyl]-6H-pyrido -[2,3-b]-[1,4]-benzodiazepine-6-one; and their salts with inorganic or organic acids. 5. Physiologically tolerable salts with inorganic or organic acids, characterized by the fact that they are salts of compounds according to claims 1 to 4. 6. Medicinal preparations, characterized by the fact that, in addition to the usual carriers and/or auxiliary substances, they contain at least one condensed diazepinone according to claims 1 to 4 or a physiologically tolerable salt according to claim 5. 7. The use of condensed diazepinones according to claims 1 to 5, characterized by the fact that they are used for the preparation of drugs for the treatment of cerebral blood flow disorders caused by arteriosclerosis, i.e. for the treatment of diseases of the central nervous system. 8. The use of condensed diazepinones according to claims 1 to 5 and 7, characterized in that they are used for the preparation of drugs for increasing the ability to learn and improving memory. 9. Process for the preparation of new condensed diazepinones of the general formula I according to claims 1 to 5, characterized in that a) basic substituted condensed diazepinone of general formula II [image] in which X, B, 1, m, n and R1 are defined as in claim 1, chemically converted with a carboxylic acid of the general formula III [image] in which R2 is defined as in claim 1, or with its derivative capable of reaction, in a solvent and at a temperature up to the boiling point of the reaction mixture, or b) diazepinone of general formula IV [image] in which X and B are defined as in claim 1, is chemically converted with a carboxylic acid derivative of the general formula V [image] in which 1, m, n, R1 and R2 are defined as in claim 1 and Nu represents a nucleophilic group, in the solvent, and the obtained compounds of the general formula I are then, if desired, separated into their diastereomers, i.e. enantiomeric forms and/or the obtained salts are converted into free bases and/or the resulting free bases are converted into their acid addition salts, especially into their physiologically tolerable salts with inorganic or organic acids.